EP0423301A1 - Synthetische peptide des konjugates von ubiquitin und histon h2a. - Google Patents

Synthetische peptide des konjugates von ubiquitin und histon h2a.

Info

Publication number
EP0423301A1
EP0423301A1 EP90907150A EP90907150A EP0423301A1 EP 0423301 A1 EP0423301 A1 EP 0423301A1 EP 90907150 A EP90907150 A EP 90907150A EP 90907150 A EP90907150 A EP 90907150A EP 0423301 A1 EP0423301 A1 EP 0423301A1
Authority
EP
European Patent Office
Prior art keywords
group
peptide
lys
gly
leu
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP90907150A
Other languages
English (en)
French (fr)
Other versions
EP0423301B1 (de
Inventor
Serge Plaue
Sylviane Muller
Reganmortel Marc Van
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bio Rad Innovations SAS
Original Assignee
NEOSYSTEM SA
NEOSYSTEM SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by NEOSYSTEM SA, NEOSYSTEM SA filed Critical NEOSYSTEM SA
Priority to AT90907150T priority Critical patent/ATE100820T1/de
Publication of EP0423301A1 publication Critical patent/EP0423301A1/de
Application granted granted Critical
Publication of EP0423301B1 publication Critical patent/EP0423301B1/de
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the subject of the present invention is peptides capable of being recognized by the antibodies present in biological fluids, in particular the seru s of patients or animals suffering from autoimmune diseases such as Systemic Lupus Erythematosus (LED) or diseases of the nervous system such than Alzheimer's or Parkinso’s disease.
  • autoimmune diseases such as Systemic Lupus Erythematosus (LED)
  • LED Systemic Lupus Erythematosus
  • Alzheimer's or Parkinso’s disease peptides capable of being recognized by the antibodies present in biological fluids, in particular the seru s of patients or animals suffering from autoimmune diseases such as Systemic Lupus Erythematosus (LED) or diseases of the nervous system such than Alzheimer's or Parkinso’s disease.
  • LED Systemic Lupus Erythematosus
  • the invention also relates to the applications of these peptides and of the compositions containing them for the in vitro diagnosis in humans of the potential of certain autoimmune or nervous system diseases, as well as their use in the constitution of diagnostic kits or "kits” .
  • the invention further relates to the applications of these peptides to the production of immunogenic compositions and vaccine compositions against these diseases.
  • the invention relates to the antibodies capable of being induced in vivo by these immunogenic peptides or rendered immunogenic and the application of these antibodies and compositions containing them for the in vitro diagnosis in humans suffering from autoimmune or nervous system diseases. , as well as the production of drugs against these diseases.
  • ubiquitin can be present in cells both freely or in combination with a large number of proteins in the nucleus, cytoplasm or membrane or also associated with the network of microtubules.
  • the cytosol ubiquitin conjugates are known to be selective mediators for the breakdown of damaged or abnormal proteins.
  • histones H2A and H2B conjugated with ubiquitin are present at rates of 10% and 1% respectively.
  • peptides are therefore applicable to the diagnosis of Systemic Lupus Erythematosus and more broadly to all autoimmune or nervous system diseases in which the conjugate of ubiquitin with the histone H2A intervenes.
  • the work carried out on these peptides made it possible to demonstrate their immunogenic interest or to be made immunogenic in order to induce in vivo the production of antibodies capable of recognizing the conjugate of ubiquitin with histone H2A, which conjugate seems to play an important role in the appearance of autoantibodies in Systemic Lupus Erythematosus, hence the very indicated use of these peptides for the preparation of vaccines against these types of diseases.
  • the peptides according to the invention have immunological properties in common with the peptide corresponding to the following formula: Gly-Gly-Arg-Leu Lys-Lys-Thr-Glu (I)
  • Preferred peptides according to the invention correspond to the following formula:
  • .X and Y represent either a free NH2 group or amidated by one or two alkyl groups comprising from 1 to 5 carbon atoms, or a peptide group comprising from 1 to 10 amino acid residues of which the N-terminal amino acid has a free or amidated NH2 group as before.
  • Z represents either a free or alkoxylated OH group and then containing an alkyl group comprising from 1 to 5 carbon atoms, or a peptide group comprising from 1 to 10 amino acid residues of which the C-terminal amino acid present in the OH group free or alkoxyl as before.
  • the groups of 1 to 10 amino acid residues contained in X and / or Y and / or Z are chosen so as to essentially preserve the immunological properties of the peptide of formula (I).
  • the sequence Gly-Gly-Arg-Leu corresponds to the sequence fraction of ubiquitin and the sequence Lys-Lys-Thr-Glu corresponds to the sequence fraction of histone H2A, at the level of the connection between these two compounds in the conjugate of ubiquitin with histone H2A.
  • the groups of 1 to 10 amino acid residues contained in X and / or Y and / or Z may in particular correspond to the contiguous amino acid residues of the peptide of formula (I) in the conjugate of ubiquitin with l 'histone H2A.
  • Y represents either a free NH2 group or a Tyr residue having a free NH2 group
  • X represents a Cys residue whose amino function is optionally acetylated
  • Z represents an OH group.
  • .Y represents either a free NH2 group or a Tyr residue having a free NH2 group
  • X represents the chain of the two residues Leu and Pro, the Pro residue being linked by a peptide bond to the contiguous Lys residue of X in the formula ( II) and the amino function of the Leu residue being optionally acetylated
  • Z represents an OH group.
  • the invention specifically envisages the peptides corresponding to the following formulas:
  • the invention relates to peptides modified by insertion and / or deletion and / or substitution of one or more amino acids, provided that the antigenic or immunogenic properties of said peptides are not modified, as well as those in which the peptide bond (-CO-NH-) is replaced for example by the following structures: -CO-N (CH3) -, -CH2-CH2-, -CO-CH2-, or in which the peptide backbone has one or several interleaved groups such as the -CH2- groups, -NH-, -O-.
  • the present invention also encompasses peptides in which the amino acid residues having an asymmetric carbon are in D or L form.
  • the peptides according to the invention can be prepared by conventional peptide synthesis techniques in solid phase either by successive condensation of the amino acid residues in the required order, or by condensation of the amino acid residues on a previously formed fragment and already containing several amino acids in the appropriate order or by condensation of several previously prepared fragments, taking care to protect beforehand all the reactive functions carried by the amino acid residues or the fragments, except the amino and carboxyl functions involved in the peptide bond formed during condensation.
  • the residue Glu the amino function of which is protected by a terbutyloxycarbonyl group
  • the residue Glu is fixed on a resin, via its carboxylic group, then after having deprotected the amino function by washing the resin with trifluoroacetic acid in dichloromethane, the second amino acid residue, the amino function of which is protected as before, is coupled in dimethylformamide, the amino acid residues which then go one after the other constitute the portion of the peptide according to the invention corresponding to the sequence fraction of histone H2A.
  • the amino function of the N-terminal residue can be acetylated by the action of an excess of acetic anhydride in the presence of diisopropylethylamine.
  • side chains of trifunctional amino acids should be protected, for example, by the following groups: cyclohexyl for glutamic acid, benzyl for threonine, tosyle for arginine, paramethylbenzyl for cysteine, 2,6-dichlorobenzyl for tyrosine, fluorenylmethyloxycarbonyl for one lysines and 2-chlorobenzyloxycarbonyl for the other lysine.
  • the side chain of lysine to which the connection is made is advantageously protected by a fluorenylmethoxycarbonyl group, after deprotection thereof with a mixture of piperidine and dimethylformamide, the first glycine residue corresponding to the sequence fraction of l is coupled as above.
  • 'ubiquitin from which we couple step by step the amino acids which will constitute the peptide chain on the amino group each time deprotected beforehand, the portion already formed remaining attached to the resin.
  • the peptide according to the invention is released from the solid support, for example with fluorydric acid.
  • the crude product is lyophilized and subjected to a liquid phase chromatography at medium pressure allowing a pure product to be obtained at approximately? 5%, these are then characterized by high pressure liquid phase chromatography as well as by the analysis of their amino acid composition and mass spectrometry.
  • the molecular mass of the peptides of formulas (II) and (III) confirmed by mass spectrometry using the FAB method are the following: the calculated values are in parentheses.
  • the invention also relates to the conjugates obtained by coupling the peptides according to the invention to carrier molecules which are optionally physiologically acceptable and non-toxic.
  • the peptides corresponding to formula (II) in which Y represents a Tyr residue can be advantageously conjugated to a carrier protein by means of bis-diazobenzidine.
  • the peptides corresponding to formula (II) in which X represents a Cys residue can be conjugated to a carrier molecule or to a support thanks to the thiol group.
  • carrier molecule As carrier molecule, mention may be made of natural proteins such as tetanus toxoid, albumin or albumin serums.
  • the peptides of the invention have antigenic properties and can therefore be used in diagnostic methods for determining or monitoring patients suffering from autoimmune or nervous system diseases in which the conjugate of ubiquitin with the histone H2A is involved.
  • the invention also relates to a composition containing at least one of the peptides capable of being recognized by the autoantibodies present in the serum or any other biological fluid of patients suffering from one of these diseases. Detection of peptide-antibody complex in living r ro is performed by immmunoenzymatiques tests of ELISA type of immunofluorescence, radioimmunoassays or radioimmunoprecipitation.
  • the invention also relates to the peptides according to "the invention marked with the aid of an adequate marker which may be biotin or its derivatives, an enzyme such as peroxidase, a fluorescent label such as fluorescein, a radioactive label such as a radioisotope, etc.
  • an adequate marker which may be biotin or its derivatives, an enzyme such as peroxidase, a fluorescent label such as fluorescein, a radioactive label such as a radioisotope, etc.
  • Such tests include, for example, the following steps:
  • the invention also relates to the antibodies formed against the peptides of the invention.
  • Antibodies which may be polyclonal, or monoclonal and then produced by any hybridoma prepared according to conventional methods of cell fusion between spleen cells of an animal immunized against one of the peptides of the invention and cells of a cell line myeloma.
  • Rabbit antisera were prepared from the peptide of formula (IV) conjugated to ovalbumin, the antibodies obtained do not react with ubiquitin nor with histone H2A in enzyme-linked immunosorbent assays of the ELISA type. By immunoblotting techniques, these antibodies made it possible to show that the contaminating fractions of 43 and _ 52 kilodaltons corresponded to conjugates of ubiquitin with the histone H2A.
  • the antibodies prepared from these peptides constitute very specific probes of the conjugates of ubiquitin and of the histone H2A incapable of binding ubiquitin or l histone H2A free.
  • the antibodies according to the invention allow the conjugate to be identified unequivocally.
  • the antibodies formed against the peptides of the invention and the autoantibodies of patients reacting with said peptides and obtained after affinity chromatography can be used to prepare anti-idiotypic antibodies constituting in part an exact copy of the initial antigenic peptide and therefore capable of binding to the autoantibodies observed in autoimmune diseases.
  • the present invention also relates to these anti-idiotypic antibodies and the compositions containing them as well as their application for the in vitro diagnosis in humans of the presence of autoantibodies and the production of a drug against autoimmune diseases.
  • the invention also relates to immunogenic compositions for the production of vaccines, the active principle of which consists of at least one peptide or an anti-idiotype antibody according to the invention, optionally conjugated to a carrier molecule, inducing the production of antibodies against said molecules.
  • peptides and which are capable of interfering with the pathology and / or clinical manifestations of autoimmune diseases are capable of interfering with the pathology and / or clinical manifestations of autoimmune diseases.
  • Pharmaceutical compositions, according to the invention which can be used as a vaccine, are constituted by solutions or suspensions which are injectable or which can be administered by other routes which can be administered at doses between 10 ⁇ g / kg and 100 mg / kg of peptides according to the invention.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biophysics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Peptides Or Proteins (AREA)
EP90907150A 1989-04-26 1990-04-23 Synthetische peptide des konjugates von ubiquitin und histon h2a Expired - Lifetime EP0423301B1 (de)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT90907150T ATE100820T1 (de) 1989-04-26 1990-04-23 Synthetische peptide des konjugates von ubiquitin und histon h2a.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR8905531A FR2646425B1 (fr) 1989-04-26 1989-04-26 Peptides synthetiques du conjugue de l'ubiquitine et de l'histone h2a
FR8905531 1989-04-26

Publications (2)

Publication Number Publication Date
EP0423301A1 true EP0423301A1 (de) 1991-04-24
EP0423301B1 EP0423301B1 (de) 1994-01-26

Family

ID=9381149

Family Applications (1)

Application Number Title Priority Date Filing Date
EP90907150A Expired - Lifetime EP0423301B1 (de) 1989-04-26 1990-04-23 Synthetische peptide des konjugates von ubiquitin und histon h2a

Country Status (6)

Country Link
US (2) US5427958A (de)
EP (1) EP0423301B1 (de)
JP (1) JPH03505590A (de)
DE (1) DE69006306T2 (de)
FR (1) FR2646425B1 (de)
WO (1) WO1990012806A1 (de)

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WO2003086273A2 (en) * 2002-04-08 2003-10-23 Yissum Research Development Company Of The Hebrew University Of Jerusalem Histone conjugates and uses thereof
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Also Published As

Publication number Publication date
JPH03505590A (ja) 1991-12-05
DE69006306D1 (de) 1994-03-10
FR2646425B1 (fr) 1991-08-30
US5545718A (en) 1996-08-13
DE69006306T2 (de) 1994-08-04
EP0423301B1 (de) 1994-01-26
FR2646425A1 (fr) 1990-11-02
WO1990012806A1 (fr) 1990-11-01
US5427958A (en) 1995-06-27

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